Recently emerged omicron subvariant BF.7 and its R346T mutation in the RBD region reveal increased transmissibility and higher resistance to neutralization antibodies: need to understand more under the current scenario of rising cases in China and fears of driving a new wave of the COVID-19 pandemic
Authors: Chiranjib Chakraborty, Manojit Bhattacharya, Hitesh Chopra, Prosun Bhattacharya, Md. Aminul Islam, Kuldeep Dhama
Journal: International Journal of Surgery (2023)

Dear Editor, About 1 year earlier, the Omicron variant (B.1.1.529) was first identified in Botswana on 9 November 20211,2. Subsequently, the variant spread throughout South Africa. Afterwards, this variant spread very quickly through the world. Scientists noted a higher amount of transmissibility than other variants and also observed reduced pathogenicity3. Suzuki and colleagues observed about 3.31-fold higher transmissibility compared to the Delta variant. The researchers found that the spike (S) protein of Delta was cleaved into two subunits proficiently, and it caused cell–cell fusion. They noted that the spike protein of Omicron was cleaved less efficiently compared to Delta's spike or wild-type SARS-CoV-24. However, several sublineages of the Omicron variant have rapidly emerged after the emergence of the Omicron. The emerging subvariances are BA.2, BA.2.75, BA.2.75.2, BA.2.12.1, BA.3, BA.4, and BA.51,5–7. Other recently emerged important Omicron subvariants are BQ.1, BQ.1.1, BA.4.6, BA.2.75.2, XBB.1, and BF.7, which have attracted global attention with fears of a rise in coronavirus disease-2019 (COVID-19) cases that could feasibly pose an alarming new wave of surges in cases amid the ongoing COVID-19 pandemic8. Of note, presently more than 650 million confirmed cases and over 6.6 million deaths have been reported due to COVID-19 as of 23 December 2022, and a start of a rise in cases is being witnessed in a few countries due to the emergence of newer subvariants of Omicron9. Few of the most recently emerged Omicron subvariants have revealed accumulated additional spike mutations, relatively higher transmissibility, and humoral immune evasion leading to a lower neutralization ability of COVID-19 vaccines and booster shots-induced protective immunity10–12. All people thought that the COVID-19 pandemic was going to end. However, at this point, a higher number of COVID-19 cases per day are being recorded in China. A new subvariant of Omicron was identified as BF.7, creating China's present surge. The subvariant was also identified in other parts of the globe, such as India, Brazil, the USA13. This newer subvariant made everybody concerned throughout the world. A recent modeling study through simulations forecasted that there might be one million deaths in China during the next few months. The researchers tried to calculate and include only deaths due to direct COVID-19 infection. The researchers did not consider the surplus deaths due to hindrances in treating people with non-COVID-19 diseases. However, they have recommended COVID-19 vaccination dosages for the people14. However, the current COVID-19 surge might be significant in terms of cumulative deaths. Recent Nature journal news also highlighted China's death-related forecast model regarding the current COVID-19 surge in China15. The Omicron variant (B.1.1.529) has about 50 mutations throughout the genome and about 32 mutations in the spike protein. About 55 mutations have been recorded in the BF.7 subvariant of Omicron throughout the genome. Thirty two mutations have been detected in the S-protein encoding gene of BF.7 subvariant. Similarly, other than spike mutations, some mutations in the BF.7 subvariant in the structural genes are: one mutation in E, three mutations in M, one in ORF8, and six in the N gene. At the same time, the researcher noted nonstructural gene mutations, which are ORF1a having eight mutations, ORF1b having four mutations, and one mutation each in ORF8 and ORF3a. The BF.7 subvariant carries a significant mutation, R346T, along with the other mutations in the S-protein. This mutation was also observed in BF.7's 'parent' subvariant BA.5 which was linked with increasing the viral capability to escape neutralizing antibodies (nAbs) induced by vaccination or earlier infection. The mutation has also been found in a particular residue (R346) in the Omicron subvariant BA.5. Several researchers have also reported mutations (R346T, R346S, or R346S) in subvariant BA.5. Arora and colleagues reported the mutation in the sublineage of BA.5 at the residue of R346, which are R346T or R346S. The mutation is found within the S-protein's receptor-binding domain (RBD) domain. The researchers have detected an increased frequency of infectivity of subvariant BA.5 due to the mutation. Mutations at R346T, R346S, or R346S might enhance resistance to nAbs, augment infectivity, or both16. A model was developed using the SARS-CoV-2 pseudovirus particles (pp) and has been used to understand the virus and host cell entry and its neutralization, adopted from Schmidt et al.'s study17. They have found reduced host cell entry by BA.4/5 (R346T, R346S, or R346S) pp compared to BA.4/5pp. The reduction was noted at around 1.6 times16. However, BF.7 contains the R346T mutation. Another study by Qu et al.10 has demonstrated antibody-mediated immune evasion by some mutations (D1199N, F486S, K444T, and R346T) for Omicron subvariants BA.2.75.2, BF.7, BA.4.6, BQ.1.1, and BQ.1. However, Qu et al.10 study indicated that the mutation R346T is present in the RBD region of the BF.7 and that it is responsible for antibody-mediated immune evasion, and other mutations (D1199N, F486S, and K444T) are not associated with the BF.7 subvariant. At the same time, our in-silico analysis shows the R346T mutation location in the RBD region along with the other spike protein mutations (Fig. 1A, B). Our in-silico analysis and heat map-related representation also demonstrate that the mutation is present in the BF.7 subvariant with a high frequency compared to other subvariants of Omicron such as BA.2, BA.2.12.1, BA.2.75, BA.2.75.2, BA.3, BA.4, and BA.5 (Fig. 1C, D).Figure 1: The significant spike mutations in the BF.7 subvariant and heatmap-like representation to compare the spike mutations frequency of subvariants of Omicron such as BF.7, BA.2, BA.2.12.1, BA.2.75, BA.2.75.2, BA.3, BA.4, and BA.5. (A) The significant spike mutations in the BF.7 subvariant ad their location in the spike protein. (B) The critical spike mutation R346T location in the receptor-binding domain region. The R346T mutation is responsible for the increased transmissibility and higher neutralization resistance of neutralizing antibody. (C) A heatmap-like representation indicates that the R346T mutation in high frequency in BF.7 compared to other subvariants BA.2, BA.2.12.1, BA.2.75, BA.2.75.2, BA.3, BA.4, and BA.5 which was developed through the in-silico analysis. A heatmap shows the spike mutation from T19I to K417N. An arrow located the R346T mutation in the heatmap-like representation. (D) Another heatmap-like representation indicates that the rest of the spike mutations' (N440K–D1199N) frequency in subvariants BF.7, BA.2, BA.2.12.1, BA.2.75, BA.2.75.2, BA.3, BA.4, and BA.5. The figure developed through the in-silico analysis. A heatmap shows the spike mutation from N440K to D1199N. Figures 1C and 1D were developed through the National Genomics Data Center (NGDC)'s RCoV19 Database from China.The basic reproductive number R0 plays a significant role in understanding the transmissibility or contagiousness of a pathogen over time. R0 is often calculated to assess public health or epidemiology-related issues18. The Omicron was noted to have an average R0 of 5.08, while BF.7 is assumed to have an R0 of 10–18.6. It might be increasing the transmission, infectivity, etc. The R346T mutation might play a significant role in increasing the R0 for BF.7. There is an urgent need to understand more about the impact of the R346T mutation to unfold the mutation's properties in emerging SARS-CoV-2 subvariants. At the same time, the significant biological properties of subvariant BF.7 and related mutations should be understood more and more. A model should be developed to calculate the R0 for BF.7 and the associated mutation. At the same time, a significant question needs to be solved: Is the increased transmissibility and higher neutralization resistance of nAbs related to a single mutation (R346T) or to the synergistic effect of other mutations? We urge the researchers to understand immediately and unfold the molecular mechanism related to the translated enhanced transmissibility and higher neutralization resistance of emerging subvariants and lineages of Omicron with the consequent gain in ability to invade people with existing immunity, so as to effectively control the spread of the subvariants by formulating adequate and tailored mitigation strategies to avoid further surges in cases and counter any new wave of COVID-19 at global level amid the ongoing pandemic. Considering the earlier deadly COVID-19 pandemic waves, which resulted in a huge surge in cases and cumulative deaths along with adverse socioeconomic impacts, we need to be fully prepared and act proactively to avoid any new dangerous COVID-19 wave. There is an urgent need for enhancing surveillance and monitoring for timely knowledge of the emergence status of Omicron subvariants and adopting strict vigilance while implementing recommended COVID-19 appropriate behavior and safety measures strictly, including wearing a face mask, regular hand washing, promoting vaccination campaigns, administering boosters, developing newer and more effective vaccines, updating vaccination strategies to match newly emerged circulating variants and subvariants, and strengthening one's health approach to counter the COVID-19 pandemic in a holistic way. Ethical approval This article does not require any human or animal subjects to acquire such approval. Sources of funding This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author contribution C.C. and M.B.: prepared draft and supervised the study. H.C., P.B., and K.D.: review and editing. M.A.I.: supervision. Conflicts of interest disclosure All authors report no conflicts of interest relevant to this article. Research registration unique identifying number (UIN) Name of the registry: not applicable. Unique identifying number or registration ID: not applicable. Hyperlink to your specific registration (must be publicly accessible and will be checked): not applicable. Guarantor Md. Aminul Islam, COVID-19 Diagnostic Lab, Department of Microbiology, Noakhali Science and Technology University, Noakhali 3814, Bangladesh. E-mail: [email protected] Data statement The data in this correspondence article is not sensitive in nature and is accessible in the public domain. The data is therefore available and not of a confidential nature. Provenance and peer review Not commissioned, internally peer-reviewed.